EP2457571A1 - Combinaisons de blocage des récepteurs dopaminergiques d2 avec inhibition de la recaptation de la norépinéphrine et blocage des récepteurs de norépinéphrine alpha 2 - Google Patents

Combinaisons de blocage des récepteurs dopaminergiques d2 avec inhibition de la recaptation de la norépinéphrine et blocage des récepteurs de norépinéphrine alpha 2 Download PDF

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Publication number
EP2457571A1
EP2457571A1 EP12156587A EP12156587A EP2457571A1 EP 2457571 A1 EP2457571 A1 EP 2457571A1 EP 12156587 A EP12156587 A EP 12156587A EP 12156587 A EP12156587 A EP 12156587A EP 2457571 A1 EP2457571 A1 EP 2457571A1
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Prior art keywords
composition
alcohol
norepinephrine
dopamine
receptor antagonist
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EP12156587A
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German (de)
English (en)
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Alan I. Green
David Chau
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/451—Non condensed piperidines, e.g. piperocaine having a carbocyclic group directly attached to the heterocyclic ring, e.g. glutethimide, meperidine, loperamide, phencyclidine, piminodine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/32—Alcohol-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/34—Tobacco-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
    • A61P25/36—Opioid-abuse
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • This invention relates to treating alcohol and/or other substance abuse or dependence, and to compositions used for such treatment.
  • Substance use disorder i.e., substance abuse or substance dependence
  • Commonly abused substances include alcohol, cannabis and cocaine, and such abuse occurs at a rate of greater than 3 times the rate seen in the general population.
  • tobacco smoking occurs in over 75% of the patients with schizophrenia.
  • the standard or typical antipsychotic medications commonly used to treat schizophrenia do not appear to be helpful in lessening the use of substances in this population.
  • norepinephrine alpha 2 receptor blockade also a property of clozapine
  • dopamine D2 receptor blockade and norepinephrine reuptake inhibition may also be helpful in limiting alcohol (or other substance) abuse in such individuals.
  • Substances of abuse in this context include not only alcohol but also opioids, including heroin and oxyContin®, cannabis, cocaine, amphetamines, tobacco and others.
  • the combinations include: a) for the dopamine D2 receptor antagonist activity, risperidone, paliperidone, haloperidol, olanzapine, quetiapine, ziprasidone, aripiprazole, iloperidone, desmethylclozapine, fluphenazine or other drugs with D2 receptor blockade (antagonistic) properties; b) for norepinephrine reuptake blockade (inhibition), desipramine or reboxetine, or other drugs with norepinephrine reuptake inhibition properties; c) for alpha 2 antagonist activity, idazoxan and yohimbine, or other drugs with norepinephrine alpha 2 receptor antagonistic effects.
  • compositions having combinations of medications, as well as methods of therapy using combinations of medications are featured, in which the multiple activities of the medication are provided by more than one specific medicinal compound.
  • the invention generally features methods of treating and or preventing substance abuse/dependence, and alcohol abuse/dependence in particular.
  • the medications used in the invention are described above.
  • the patients to be treated according to the invention are those with a history or a risk of alcohol or substance abuse/dependence.
  • the compounds to be administered can be formulated into a suitable pharmaceutical preparation by known techniques, for example well known tablet and capsule formulations.
  • Such formulations typically comprise the active agent (or the agent in a salt form) and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable carrier is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • a pharmaceutical composition of the invention is formulated to be compatible with its intended route of administration.
  • routes of administration include oral, intravenous, intradermal, subcutaneous, transdermal (topical), transmucosal (e.g. intranasal), and rectal.
  • Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets.
  • the active compound can be incorporated with excipients and used in the form of tablets, troches, or capsules. Pharmaceutically compatible binding agents, and/or adjuvant materials can be included as part of the composition.
  • the tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.
  • a binder such as microcrystalline cellulose, gum tragacanth or gelatin
  • an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch
  • a lubricant such as magnesium stearate or Sterotes
  • a glidant such as colloidal silicon dioxide
  • the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems.
  • a controlled release formulation including implants and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art.
  • the materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc.
  • Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.
  • compositions can be included in a container, pack, or dispenser together with instructions for administration.
  • the animal models that we have used in our experiments include the Syrian golden hamster (Mesocricetus auratus, Harlan Inc.) and the alcohol preferring P rat (Indiana University). Both animals prefer an alcohol solution over water when given a choice between the two fluids and they consume large quantities of alcohol on a daily basis.
  • the hamster is an out-bred rodent, which has a natural preference for alcohol
  • the P rat has been bred over multiple generations through the selective mating of rats with high alcohol preference.
  • Both the hamster and the P rat have been used by alcohol researchers to screen medications for treatment of alcoholism. Keung, W.M. and B.L.
  • the first type of study assessed the ability of drugs (or drug combinations) to decrease chronic alcohol drinking in these animals. In these studies, drug treatment began after the animals had been drinking alcohol for several weeks.
  • the second type of study assessed the effects of drugs (or drug combinations) on the ability of the animals to initiate alcohol drinking.
  • Example 5 we have demonstrated that clozapine (in this case a low dose) also blunts the initiation of alcohol drinking in the hamster.
  • clozapine in this case a low dose
  • Figure 5 we have also demonstrated that by adding raclopride (RACL, a potent D2/D3 receptor antagonist) to a low dose of clozapine, this effect of clozapine on the initiation of alcohol drinking by the hamster is lost. This finding is consistent with our proposition that clozapine's effect on alcohol drinking is at least partially related to its weak D2 receptor blocking ability.
  • RACL a potent D2/D3 receptor antagonist
  • haloperidol has very little effect on chronic alcohol drinking.
  • DMI norepinephrine reuptake inhibitor desipramine
  • HAL low dose haloperidol
  • RISP risperidone
  • DMI norepinephrine reuptake inhibitor desipramine
  • risperidone is also a blocker of the norepinephrine alpha 2 receptor (as well as the D2 receptor), its blockade of the alpha 2 receptor (in combination with its D2 receptor blockade) may contribute to allowing DMI to convert risperidone into a drug that decreases alcohol drinking.
EP12156587A 2007-02-01 2008-02-01 Combinaisons de blocage des récepteurs dopaminergiques d2 avec inhibition de la recaptation de la norépinéphrine et blocage des récepteurs de norépinéphrine alpha 2 Withdrawn EP2457571A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US88765707P 2007-02-01 2007-02-01
US711707P 2007-12-11 2007-12-11
EP08826643A EP2114150A4 (fr) 2007-02-01 2008-02-01 Combinaisons de blocage des récepteurs dopaminergiques d2 avec inhibition de la recaptation de la norépinéphrine et blocage des récepteurs de norépinéphrine alpha 2

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EP08826643.2 Division 2008-02-01

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EP2457571A1 true EP2457571A1 (fr) 2012-05-30

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EP12156587A Withdrawn EP2457571A1 (fr) 2007-02-01 2008-02-01 Combinaisons de blocage des récepteurs dopaminergiques d2 avec inhibition de la recaptation de la norépinéphrine et blocage des récepteurs de norépinéphrine alpha 2
EP08826643A Withdrawn EP2114150A4 (fr) 2007-02-01 2008-02-01 Combinaisons de blocage des récepteurs dopaminergiques d2 avec inhibition de la recaptation de la norépinéphrine et blocage des récepteurs de norépinéphrine alpha 2

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Country Status (6)

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US (2) US9044471B2 (fr)
EP (2) EP2457571A1 (fr)
JP (1) JP2010518023A (fr)
AU (1) AU2008279572A1 (fr)
CA (1) CA2677219A1 (fr)
WO (1) WO2009014770A2 (fr)

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JPWO2016104367A1 (ja) * 2014-12-22 2017-09-28 株式会社Ｌｔｔバイオファーマ 機能性ディスペプシア治療薬
US11207322B2 (en) 2017-04-28 2021-12-28 Board Of Regents, The University Of Texas System Method and composition related to combination therapy for addiction
BR112020011189A2 (pt) 2017-12-05 2020-11-17 Sunovion Pharmaceuticals Inc. misturas não racêmicas e usos das mesmas
MX2020005517A (es) 2017-12-05 2020-11-09 Sunovion Pharmaceuticals Inc Formas cristalinas y metodos de produccion de las mismas.
US11160758B2 (en) 2019-06-04 2021-11-02 Sunovion Pharmaceuticals Inc. Modified release formulations and uses thereof
CN117338772B (zh) * 2023-11-22 2024-04-09 徐州医科大学 一种药物组合物及其在制备用于预防和/或治疗重性抑郁障碍的药物中的应用

Citations (6)

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WO2000030650A1 (fr) * 1998-11-23 2000-06-02 Sepracor Inc. Compositions de desmethylolanzapine et methodes associees
WO2000030648A1 (fr) * 1998-11-23 2000-06-02 Sepracor Inc. Compositions a base de 2-hydroxymethylolanzapine et leurs utilisations
WO2004034996A2 (fr) * 2002-10-18 2004-04-29 Massachusetts Mental Health Institute Traitement de l'abus d'alcool et/ou de substances par antagonisme vis-a-vis des recepteurs alpha2-adrenergiques avec fabile blocage de la dopamine
US20060058293A1 (en) * 2004-08-03 2006-03-16 Eckard Weber Combination of bupropion and a second compound for affecting weight loss
US20060276412A1 (en) * 2005-05-31 2006-12-07 Gary Tollefson Methods and compositions for managing psychotic disorders
US20060287299A1 (en) * 2003-12-02 2006-12-21 Sheldon Leslie J Combination therapy for dementia, depression and apathy

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JP2006071612A (ja) * 2004-09-06 2006-03-16 Niigata Tlo:Kk 学習機能障害評価方法、及び学習機能障害評価用装置
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WO2000030650A1 (fr) * 1998-11-23 2000-06-02 Sepracor Inc. Compositions de desmethylolanzapine et methodes associees
WO2000030648A1 (fr) * 1998-11-23 2000-06-02 Sepracor Inc. Compositions a base de 2-hydroxymethylolanzapine et leurs utilisations
WO2004034996A2 (fr) * 2002-10-18 2004-04-29 Massachusetts Mental Health Institute Traitement de l'abus d'alcool et/ou de substances par antagonisme vis-a-vis des recepteurs alpha2-adrenergiques avec fabile blocage de la dopamine
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US20060058293A1 (en) * 2004-08-03 2006-03-16 Eckard Weber Combination of bupropion and a second compound for affecting weight loss
US20060276412A1 (en) * 2005-05-31 2006-12-07 Gary Tollefson Methods and compositions for managing psychotic disorders

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Also Published As

Publication number Publication date
CA2677219A1 (fr) 2009-01-29
WO2009014770A2 (fr) 2009-01-29
AU2008279572A1 (en) 2009-01-29
US9044471B2 (en) 2015-06-02
JP2010518023A (ja) 2010-05-27
EP2114150A2 (fr) 2009-11-11
WO2009014770A3 (fr) 2009-03-12
EP2114150A4 (fr) 2010-03-10
US20080188464A1 (en) 2008-08-07
US20150374712A1 (en) 2015-12-31

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